Structural analogs of S-adenosylhomocysteine will be synthesized and evaluated as inhibitors of S-adenosylmethionine-dependent methyltransferases in an effort to detect differences in the structural requirements needed to bind to the active sites of these enzymes. The enzymes which will be utilized for in vitro studies include catechol-O-methyltransferase (COMT), phenethanolamine-N-methyltransferase (PNMT), histamine-N-methyltransferase (HMT), hydroxyindole-O-methyltransferase (HIOMT), indoleethylamine-N-methyltransferase (INMT) and protein methylase I and II. Each of these enzymes are important in regulating the activity of hormones or neurotransmitters (epinephrine, dopamine, norepinephrine, melatonin, protein hormones, etc.). The inhibitory activity of these SAH analogs will also be evaluated on nucleic acid methylation systems, including both rat liver t-RNA methylases and viral m-RNA methylases. With the t-RNA methylation systems the effect of SAH analogs on the specific methylation pattern of t-RNAs will be determined. In the viral m-RNA systems (vesicular stomatitus virus and Newcastle disease virus), the effects of SAH analogs on methylation of m-RNA and on protein synthesis will be examined. Studies to determine whether these SAH analogs are substrates and/or inhibitors of the SAH metabolizing enzyme adenosylhomocysteinase (mammalian systems) and SAH nucleosidase (bacterial enzymes) will also be carried out. In vivo studies will also be undertaken to evaluate the effects of SAH analogs on catecholamine metabolism (COMT), on epinephrine biosynthesis (PNMT), and on cell transforming oncogenic virus (Rous sarcoma virus). By evaluation of the SAH analogs prepared in our laboratory as inhibitors of these methyltransferase systems, it is hoped that differences in inhibitory specificity will be detected which can be used to design specific inhibitors.